This invention relates to treatment of psoriasis and other proliferative skin disorders using phototherapeutic techniques.
Psoriasis is a chronic, incurable, inflammatory skin condition affecting two to four percent of the world""s population. Severity ranges from minor to life-threatening, and often fluctuates. Pathogenesis is unknown, but involves hereditary abnormalities of the immune system, with lymphocyte and neutrophil-mediated inflammation combined with hyperplasia of the epidermis. The epidermis proliferates at about ten times the normal rate. People with psoriasis literally leave a trail of skin flakes, and suffer from chronic itchy lesions, poor temperature regulation, fatigue from constant protein loss, and social stigma to the point of reclusion. There is an associated arthritis which attacks the fingers. The most common form is plaque-type psoriasis, in which well-demarcated lesions appear on the body, with normal skin between them. The plaques are red and scaly, quite different from the surrounding normal skin. The number of plaques ranges from several to several hundred, scattered over the trunk, arms, and legs. Psoriasis tends to spare the face, because ultraviolet (UV) light is therapeutic.
There is no cure for psoriasis. Drug treatments work by anti-inflammatory, antimitotic, hormonal, or immunosuppressive mechanisms. These include topical administration of corticosteroids, tar preparations, and vitamin D3 derivatives, systemic chemotherapy with methotrexate, and immunosuppression with cyclosporin A. Topical treatments are messy and expensive, but are still the main approach for patients with small areas of involvement. Corticosteroids tend to produce partial clearing followed by a xe2x80x9creboundxe2x80x9d worse than the original disease severity, cause skin atrophy, and become progressively ineffective over time. Methotrexate is effective but causes liver toxicity. Cyclosporin A has multiple side effects, is expensive, and reserved for severe cases.
Ultraviolet phototherapy with or without photosensitizers, has been a mainstay of psoriasis treatment for many decades. UVB (290-320 nm) phototherapy is practical, effective, and often produces a long remission time after clearing, typically about five months. Psoralen, an extremely potent DNA-crosslinking photosensitizer, is also used orally or topically, followed by exposure to UVA radiation (320-400 nm). This is called Psoralen UVA (PUVA), a type of photochemotherapy. Phototherapy clears plaques in about 90% of patients, by combined mechanisms including apoptosis of keratinocytes, antimetabolic effects of DNA damage, and local and systemic immunosuppression. The patient stands in a xe2x80x9clight boxxe2x80x9d lined with fluorescent lamps or other UV sources, and receives a prescribed fluence, i.e., a therapeutic dose of radiation. Each box is the size of a phone booth and costs about twenty to thirty thousand dollars. Since psoriasis does not usually affect the face, the patient typically wears a mask covering the face and eyes to prevent exposure to the therapeutic radiation. The rate of clearing is variable between patients, and depends on the exposure dose per treatment. An average of 20 to 30 treatments is needed for UVB (given 3 times per week) and an average of 15 to 25 treatments is needed for PUVA (given 2 times per week), depending on aggressiveness of the exposure dose protocol. Hence, it takes several months and many trips to the phototherapy center to clear psoriasis.
The xe2x80x9cartxe2x80x9d of phototherapy lies in achieving clearing without causing painful sunburn-like reactions. Thus, skin unaffected with psoriasis, i.e., normal skin, limits the therapeutic dose. The minimal erythema dose (MED) in normal skin is defined as the lowest fluence eliciting an inflammatory response, and is used to guide dosimetry. If the patient receives more than 1 MED, a xe2x80x9csunburnxe2x80x9d will occur. At 3 MED a painful sunburn with blistering can occur, and at 10 MED a life-threatening burn results. Prior to a phototherapy treatment, the doctor determines the MED for a particular patient. As tanning develops during the course of multiple treatments, the UV fluence is increased, typically by 30 to 50 percent per treatment. At present, phototherapy consists of carefully but aggressively xe2x80x9cpushingxe2x80x9d the exposure dose based on response of the unaffected skin between plaques of psoriasis.
The cost of phototherapy, based on the number of trips and the clinicians"" time, is estimated to be almost 1 billion dollars per year in the US. This does not include the cost of treating of skin cancers induced by phototherapy. In particular, prolonged exposure to UVB and PUVA cause basal cell carcinoma, squamous cell carcinoma, and melanoma. These diseases typically occur in areas of skin between plaques of psoriasis that have been exposed to large cumulative doses of UV radiation during phototherapy.
The invention features methods and systems for treating inflammatory, proliferative skin disorders, such as psoriasis, with ultraviolet phototherapy. The methods and systems use optical techniques to scan a patient""s skin, designate areas of affected skin, and selectively deliver high doses of phototherapeutic ultraviolet radiation to the designated areas. The high dose levels are typically greater than two minimal erythema doses (MED) and often about ten MED. These dose levels are very effective at treating affected areas of skin, but would badly damage unaffected areas of skin, e.g., normal skin. To insure that only areas of skin affected by psoriasis or other disorders are designated for the high doses of UV radiation, the methods and systems use one or more optical diagnostics that relate to independent physiological features of affected skin.
The methods can be implemented by a system, e.g., a robotic system, that scans a patient""s skin and constructs a digital map designating affected areas of skin based on one or more optical diagnostics. After a doctor or technician reviews, and possibly modifies, the digital map, the robotic system delivers the phototherapeutic radiation doses to the areas of skin designated by the map.
Alternatively, the automated designation of affected areas of skin and the selective delivery to the designated areas can be implemented with a manual device such as a fiber optic pen or comb. In such cases, a surgeon scans the patient""s skin with the device to designate affected areas of skin. The treatment can be performed in real time based on the designation or, alternatively, the designation can be used to construct a digital map of the affected areas to guide subsequent treatment.
In general, the invention features a method for treating a proliferative skin disorder, e.g., psoriasis, in a patient by exposing the patient""s skin to radiation; detecting at least one optical diagnostic signal in response to the radiation from a selected area of the patient""s skin; determining from the optical diagnostic signal whether the selected area is affected by the skin disorder; and if the selected area is determined to be affected by the skin disorder, delivering an effective dose of phototherapeutic radiation to the selected area, e.g., using a laser, such as a xenon chloride excimer laser. The method can be automated. The selected area can be less than about 1 cm2.
In specific embodiments, the phototherapeutic radiation is ultraviolet radiation having a wavelength of about 290 nm to 330 nm, and the effective dose is in the range of about 0.02 J/cm2 to 1 J/cm2. The effective dose can be greater than about two, three, five, or even ten minimal erythema doses (MED). The optical diagnostic signal can relate, or correspond, to diffuse reflectance or fluorescence, for example.
In another embodiment, the exposing step can include delivering a diagnostic dose of radiation from a source, wherein the diagnostic dose is sufficient to excite the fluorescence from the selected area, but is not an effective dose of phototherapeutic radiation, and wherein the delivering step includes delivering an effective phototherapeutic dose of radiation from the source by increasing fluence of the source.
The new method can further include detecting at least one additional optical diagnostic signal from the selected area; and determining from all of the signals whether the selected area is affected by the skin disorder. For example, at least two of the signals can relate to different physiological properties of the skin disorder. The method can further include constructing a digital map of areas of the patient""s skin affected by the skin disorder by repeating the detecting and determining steps for additional selected areas; and delivering effective doses of phototherapeutic radiation, e.g., ultraviolet radiation, to at least one, some, or all of the affected areas indicated on the map.
In addition, the method can further include detecting an additional optical diagnostic signal from each of the areas indicated on the map to confirm that these areas are affected and designating the confirmed areas as treatment areas; and delivering an effective dose of phototherapeutic radiation to at least one of the treatment areas. For example, the constructing step can be completed before the delivering step.
In another aspect, the invention features a system for treating a proliferative skin disorder in a patient. The system includes an illumination source configured to irradiate the patient""s skin; a detector configured to receive optical radiation emitted from selected areas of the patient""s skin in response to the irradiation from the illumination source and to generate a signal relating to the radiation received from each of the selected areas (for example, the measured signal can include data relating to at least two different physiological features of the skin disorder); an analyzer connected to the detector, wherein the analyzer compares the signals from the selected areas to at least one threshold parameter and designates selected areas having measured signals above the threshold parameters as affected areas; and a source, e.g., a xenon chloride excimer laser, configured to deliver doses of therapeutic radiation designated by the analyzer.
In this system, the detector can measure diffuse reflectance and fluorescence and the analyzer can compare the signals relating to the diffuse reflectance and fluorescence to the at least one threshold parameter to designate the affected areas. In addition, the analyzer can normalize the measured signals when comparing them to the at least one threshold parameter.
Also, an automated positioning system can be connected to the analyzer and used to control the delivery of the doses from the source to the affected areas of skin designated by the analyzer. Alternatively, the analyzer can cause, e.g., directly cause, the therapeutic source to deliver the doses of therapeutic radiation to the affected areas of skin, e.g., through a manual instrument.
For example, the system can include a manual instrument connected to the therapeutic source and the detector such that the instrument delivers the optical radiation emitted from the selected areas of the patient""s skin to the detector and delivers the doses of therapeutic radiation from the therapeutic source to the affected areas. In some embodiments, the manual instrument can be further connected to the illumination source to deliver illumination radiation to the patient""s skin from the illumination source. The manual instrument can include one or more optical fibers through which the detector receives the optical radiation emitted from the selected areas of the patient""s skin, and through which the therapeutic source delivers the doses of therapeutic radiation. The manual instrument can be in the shape of a pen or a comb. Also, the manual instrument can include a position sensor, which during operation sends a position signal to the analyzer to indicate a relative position of the instrument with respect to the patient. For example, the position sensor can be a tracking ball that rolls along the patient""s skin as a doctor or technician positions the instrument.
A minimal erythema dose (MED) is defined as the lowest fluence eliciting an inflammatory response in normal skin. The MED varies from patient to patient and depends on natural skin color, as well as other factors, such as age and skin thickness. At 310 nm, the MED for Caucasians typically varies from about 0.05 to 0.30 J/cm2, and the amount of energy required to provide one MED is higher in people having darker skin.
Measurement of diffuse reflectance is defined as measurement of a light component reflected from within the surface of a reflecting object. Multiple scattering within the object tends to depolarize the light component. To measure diffuse reflectance, one typically measures polarized light reflected from an object illuminated with orthogonally polarized light.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Embodiments of the invention include many advantages. For example, the methods and systems selectively deliver radiation to only those areas of skin affected by psoriasis, thereby reducing risks such as sunburn (acute risk) and skin cancer (chronic risk), which are inherent in present phototherapy methods. For example, scrotal cancer is about 200 times higher in patients subject to present phototherapy methods.
Furthermore, the methods and systems allow large doses of radiation to be delivered to the affected areas, which increases the effectiveness of the phototherapy. Furthermore, for these affected areas, skin cancer risk is reduced since only a few high-dose radiation treatments are used in place of many low-dose radiation treatments. Epidemiologic studies suggest that skin cancer risk is lower when a higher dose-per-treatment and lower cumulative dose is used.
Also, the methods and systems greatly reduce the number of treatments necessary to clear the psoriasis, from about 25 to about 5 to 10. The cost of psoriasis phototherapy is dominated by the number of treatments needed for clearing. As a result, in the United States, for example, the invention could save over one half of the annual phototherapy cost of about one billion dollars. The methods and systems also reduce the space and time required for each individual treatment, further reducing phototherapy costs. For example, since only affected areas are being treated, a doctor need not need be concerned about sunburning unaffected skin. Thus, before each treatment, the doctor need not determine the amount of radiation corresponding to one MED, as in traditional phototherapy.
Finally, the methods and systems automate the detailed and meticulous tasks of designating and selectively treating only those areas of skin affected by psoriasis or other disorders. The use of multiple diagnostics, which monitor different physiological features of skin, insures that areas of skin designated by all of the diagnostics are indeed affected, e.g., by psoriasis. The multiple diagnostics thereby prevent delivery of high-dose, and potentially harmful, radiation to unaffected areas of skin.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.